Open Access

ARTICLE

Inhibition of focal adhesion kinase by antisense oligonucleotides enhances the sensitivity of breast cancer cells to camptothecins

by T.H. Satoh, T.A. Surmacz, O. Nyormoi, C.M. Whitacre

1. School of Natural and Health Sciences, Barry University, 11300 N.E. Second Ave., Miami Shores, FL 33161, USA.
2. Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, 4200 E. Ninth Ave., Denver, CO 80262, USA.
3. Max-Planck Research Unit Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle (Saale), Germany.
4. Department of Cancer Biology, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Address correspondence to: Cecilia Merched Whitacre, Ph.D. School of Natural and Health Sciences, Barry University, 11300 M.E. Second Avenue, Miami Shores, FL 33161-6695, USA. Fax: (+1-305) 899 3225. E-mail: cmerched@mail.barry.edu

BIOCELL 2003, 27(1), 47-55. https://doi.org/10.32604/biocell.2003.27.047

Abstract

This study shows a strong association between cell attachment to substratum and activation of β1-integrin-signaling with resistance to the camptothecin derivative topotecan (TPT) in breast cancer cells. We propose a mechanistic-driven approach to sensitize the cells to camptothecins. ZR-75-1 anchoragedependent breast cancer cell line, its derivative 9D3S suspension cells (9D3S-S), and 9D3S cells attached to fibronectin-coated plates (9D3S-A) were treated with TPT (1 µM) or CPT-11 (40 µM) for 48 h. Programmed cell death (PCD), as shown by poly(ADP-ribose) polymerase (PARP), pro-caspase-3 and pro-caspase-9 cleavage, was observed in 9D3S-S cells but not in ZR-75-1 or 9D3S-A cells. Because p125 focal adhesion kinase (FAK) is a transducer in the β1-integrin signaling pathway, it is essential to cell adhesion and it is overexpressed in metastatic breast cancer, we hypothesized that attenuation of FAK might enhance the sensitivity of breast cancer cells to camptothecins. Moreover, inhibition of FAK gene expression by a phosphorothioated antisense oligodeoxynucleotide targeting the portion of the gene encoding amino acids 262-268, increased the sensitivity of ZR-75-1, MDA-MB-231 and MCF7 breast cancer cells to treatment with TPT or CPT-11.

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